The chief clinical manifestation of osteoporosis is the occurrence of fractures. Most'osteoporotic fractures oc- cur at skeletal locations rich in trabecular bone. Prevailing among these are the vertebrae, wrist and proximal femur. There is now strong evidence that the loss of bone mass is accompanied by a decline in the trabecular bone network's structural integrity. The impaired mechanical competence secondary to gonadal steroid de- pletion is largely due to topological changes in the bone's architectural make-up, chatacterized by fenestra- tion of trabecular plates resulting in their conversion to rods, which eventually become disconnected. The in- vestigators have provided in vivo imaging evidence in previous cycles of this ongoing project in support of such an etiology. Complementing antiresorptive treatment, new therapies have recently become available to treat the devastating consequences of severe bone loss with bone-forming (i.e. anabolic) drugs. It is not clear, however, whether such therapies are, in fact, able to reverse the disintegration of the trabecular net- work, and to what extent the structural changes differ from those induced by antiresorptive treatment. In the new cycle of the project for which support is sought, we propose to significantly enhance our previously de- veloped MRI-based virtual bone biopsy technology to quantify the structural and mechanical consequences of two fundamentally different forms of drug treatment in patients with metabolic bone disease. We aim to apply this methodology to patients who are at high risk of fracture and who are treated either with recombinant 1-34 parathyroid hormone or alendronate. We advance the hypothesis that in vivo micro-MRI will be able to distin- guish the structural and mechanical manifestations of short-term treatment and that the method will provide new insight into the structural manifestations of trabecular bone exposed to antiresorptive and anabolic ther- apy. The project will consist of five specific aims involving the development, integration and evaluation of new methods involving data acquisition and reconstruction, motion correction, image processing and analy- sis, as well as image-based computational biomechanics.